Pony Express Protein: Protein Found That Rallies Biological Clock

A biologist at Washington University in St. Louis and his collaborators
have identified the factor in mammalian brain cells that keeps cells in
synchrony so that functions like the wake-sleep cycle, hormone secretion
and loco motor behaviors are coordinated daily.

Erik Herzog, Ph.D., Washington University associate professor of
Biology in Arts & Sciences, Sara Aton, Ph.D., a graduate student in
Herzog's lab who is now a postdoctoral researcher at the University of
Pennsylvania, James Huettner, Ph.D., associate professor in cell biology
and physiology at the Washington University School of Medicine, and
Martin Straume, a biostatistician, have determined that VIP — vasoactive
intestinal polypeptide — is the rallying protein that signals the
brain's biological clock to coordinate daily rhythms in behavior and
physiology.

The finding clarifies the roles that both VIP and a neurotransmitter
GABA play in synchronizing biological clocks, and sheds light on how
mammals, in this case mice and rats, regulate circadian rhythm. Results
were published in the Nov. 27- Dec. 1 online issue of the Proceedings of
the National Academy of Sciences.

Neurons in the biological clock, an area called the suprachiasmatic
nucleus (SCN), located at the base of the brain right across the optic
nerve, keep 24-hour time and are normally highly synchronized. The SCN
is composed of 10,000 neurons on one side of the hypothalamus, and
10,000 on the other. Together these neurons are intrinsic clocks in
communication with each other to keep 24-hour time.

It had been thought that GABA was the prime candidate for the
rallying role. All SCN neurons make this inhibitory neurotransmitter,
and it had been shown that giving GABA daily at 8 a.m. to SCN cells
synchronizes them.

"The surprise was that GABA was not needed," said Herzog. "VIP
synchronizes even when we block all GABA signaling. When we blocked
GABA, synchrony was perfectly fine. Instead, the oscillations got
bigger."

Herzog likens VIP to the Pony Express rider telling all the SCN cells
to synchronize their watches; GABA, he says, is like the marshal that
prevents the cells from being too active.

Herzog and Aton recorded neuron activity from the SCN using a
multielectrode array with 60 electrodes upon which they place SCN cells,
a "clock in a dish." They also recorded gene expression in real-time
using a bioluminescent reporter of gene activity.

Using drugs or genetic knock out mice, they negated the role of GABA
and recorded the electrical activity of many neurons, what Herzog calls
the "hands of the clock," and the gene activities, "the cogs of the
clock," of many SCN cells.

They found that, without GABA, the cells marched together, but
without VIP, they lost synchrony, indicating that VIP is the
coordinator.